Irritability is often considered the most impairing symptom of pediatric BD (1
), yet there is minimal research on its pathophysiology. Prior work demonstrated affective, behavioral, and psychophysiological deficits in BD youth in a frustration-inducing context (5
). As in that work, here we used the affective Posner task, modified by rigging feedback to induce frustration, and we now examined the neural mechanisms of frustration in BD youth using magnetoencephalography (MEG). We predicted greater ACC theta power in BD youth following negative feedback because increased ACC theta power (i.e. synchronization), which reflects neuronal activation (50
), is seen during the processing of emotional stimuli (16
Replicating our previous finding (5
), BD youth reported a more adverse affective response to negative feedback in the frustrating context than controls. While not a measure specifically of irritability, this result suggests that BD youth were more upset by the frustration-inducing condition than were controls. BD youth were also slower to respond than controls in the frustration condition, though this deficit was seen in response to both positive and negative feedback. Our MEG results indicated that, in response to frustration-inducing negative feedback, BD youth displayed greater theta power relative to controls in the right ACC and bilateral parietal lobe (i.e. left IPL and right SPL). In contrast, compared to BD youth, controls displayed greater left ACC theta power following positive feedback, with a trend in the same direction in the right ACC.
ACC-generated theta power is associated with self-monitoring and emotion processing, often in response to evaluative feedback (25
). Thus, our results suggest that, compared to controls, BD youth display heightened processing of negative feedback and exaggerated self-monitoring following this aversive stimulus. Information-processing theories (74
) would suggest that disproportionate cognitive engagement by negative stimuli, such as that seen in BD youth, might sustain and/or exacerbate negative mood (i.e. irritability and frustration). In contrast to results in BD youth, controls engaged the ACC more robustly following positive
feedback. Thus, in BD youth positive information which might otherwise diminish negative mood may be filtered out.
Our finding that ACC theta synchronization patterns in BD patients differed from controls adds to structural (29
) and functional (31
) MRI literature implicating the ACC in adult and pediatric BD. In pediatric BD specifically, data suggest ACC volumetric deficits and ACC hyperactivation during non-emotional tasks (i.e. behavioral inhibition (32
) and working memory (31
)), as well as during emotional tasks involving processing both positive (31
) and, in our study, negative stimuli. Continued work is necessary to elucidate the extent to which these patterns of ACC theta oscillations are specific to bipolar youth or frustration in general, and how variables such as age and gender impact MEG data. Developmental studies have not been conducted using MEG, and the data using other imaging techniques are mixed. For example, while some fMRI (83
) and EEG studies (84
) find greater ACC activation in adults compared to youth, a number of studies report the opposite finding (83
In addition to the ACC result, BD youth displayed greater theta power than controls in the inferior and superior parietal lobe (IPL and SPL) in response to negative feedback. The parietal patterns identified here are consistent with our previous EEG-based findings of a parietal P300 deficit in a different sample of BD youth using the affective Posner task (5
). These results, along with prior studies finding volumetric deficits (90
) and hyperactivity during attention (91
), implicate parietal perturbations in the pathophysiology of pediatric BD. In addition, our finding in BD youth of increased theta power in both the ACC and parietal lobe is consistent with prior work identifying concomitant activation of these regions. Specifically, coordinated activation of the ACC and parietal lobe is thought to reflect attention (92
) and performance monitoring, in particular in response to unexpected conflicts (93
) and feedback (95
). In sum, prior ACC-parietal results further support the suggestion that, in response to negative feedback, the neural mechanisms mediating self-monitoring and attention to emotional stimuli differ between euthymic BD youth and controls.
A strength of this study is that all BD participants were euthymic when tested. This may in part be attributable to the medicated status of most of our patients, which is our primary study limitation. Because it is unethical to discontinue medication solely for research purposes, it was not feasible for us to limit the sample to unmedicated patients. A recent MEG study of adults with schizophrenia found comparable theta activity between unmedicated patients and those receiving neuroleptic medication (96
). Previous fMRI studies with BD subjects suggest that differences between unmedicated BD subjects and controls are greater than those between medicated patients and controls (32
), suggesting that the inclusion of medicated subjects may inflate the possibility of Type II, rather than Type I, error. In addition, a previous EEG study found that psychotropic medications may reduce the power of neuronal oscillations (100
). Despite this, we documented increased theta synchronization in BD youth compared to controls, and this was specific to negative, and not positive, feedback. However, there is documentation of altered theta power resulting from lithium, (101
), mood stabilizers (104
), and serotonin-specific reuptake inhibitors (SSRIs) (107
). Clearly, additional research is needed to differentiate neural perturbations associated with BD from those associated with medication.
An additional limitation is that correlations between theta power and behavior and affect were nonsignificant. Considerable previous work demonstrates discordance among between-group differences in clinical characteristics, task-related performance, and brain function in studies of psychiatrically-impaired children, adolescents, and adults. Indeed, the current result is comparable to prior data that found inconsistent behavioral and neural results, i.e. neural differences in the absence of behavioral differences (109
), or incongruent behavioral and neural results (109
). The field continues to debate the advantages and disadvantages of performing research with tasks that do or do not generate between-group differences in behavior, in the context of brain imaging. On the one hand, some argue that the absence of group differences in task performance is preferred, because group differences in neural responses can not reflect potential subject performance deficits (116
). Other researchers, however, view differences in task performance as aiding interpretation of differences in activation (118
). This is because such differences provide on-line evidence that a perturbed behavioral response style is specifically engaged in the context of the imaging experiment. We should also note that the inconsistency in our study may also reflect methodological issues. Namely, behavior and imaging data reflect processes occurring at related but clearly differentiable points in time: behavior only was measured at one point in time, in response to targets on trials following positive and negative feedback; this was potentially 2800 ms after the continuously monitored patterns of theta responding showed between-group differences. Moreover, emotional response was measured at the completion of the 8-minute condition 3, rather than on a trial-by-trial, let alone millisecond-by-millisecond, basis. It is important for future work to explore the relative contributions of affective, behavioral, and neural data to understanding cognitive-emotional functioning in psychiatric populations.
Consistent with other neuroimaging studies of bipolar youth (30
), our patient sample presented with high rates of comorbidity, most notably ADHD and anxiety disorders. Post hoc analyses found that ADHD did not change the nature of our results, though BD subjects without anxiety failed to display the left IPL theta power deficits seen in the BD sample as a whole. However, these analyses are severely limited by the small sample size, and therefore our results should be considered preliminary. Understanding our data is also limited by the lack of strong normative population data. Future work should explore the impact of comorbid disorders and compare youth with different diagnoses (e.g. BD, ADHD, anxiety) to elucidate the specificity of neural perturbations.